OVERALL PROJECT SUMMARY Inter-cellular communication between cells within a tissue environment is fundamentally important for many physiological processes. Channels and transmembrane transporters that conduct ions and other molecules across the plasma membrane in healthy living cells are also linked to pathologies of the cardiovascular and respiratory systems. Extracellular nucleltides (such as ATP) and their derivatives, as well as other metabolites critically influence many aspects of vasculary physiology such as sympthetic nerve-induced vasoconstriction and blood pressure regulation, as well disease states such as diet-induced cardiometabolic syndromes. Recent exciting series of observations suggest that the pannexin proteins form channels on the plasma membrane, and by permeating ions and/or the release of nucleotides in a very regulated manner, these pannexin channels allow cells to communicate with other cells. Consistent with this, altered expression of pannexin channels have been linked to cardovascular and metabolic disorders. Independently, the pannexin channels also play a role in releasing nucleotides from early stage apoptotic cells that appear critical for communicating with phagocytes, and with the tissue microenvironment. The central hypothesis tested via this PO1 application is that pannexin channels sit at a critical interphase between normal homeostasis within the cardiovascular system, and the disease states leading inflammation, and hypertension. The four projects that comprise this proposal address the role of pannexin channels as follows. Project 1 (Ravichandran) addresses the role of pannexin channels in apoptotic cell:phagocyte communication, between dying cells and the neighborhood in regulating anti- inflammatory signaling, and regulating tissue inflammation; Project 2 (Isakson) addresses how pannexin channels in vascular smooth muscle cells contribute to vasoconstriction in resistance vessels to regulate blood pressure, and how Pannexin 1 links sympathetic nervous system to arterial function; Project 3 (Leitinger) addresses how pannexin channels regulate inflammation and fibrosis of the liver as part of the larger cardiometabolic syndrome; Project 4 (Bayliss) addresses molecular mechanisms of pannexin channel activation in physiological and diseased states. With the combination of mouse models and ex vivo studies, and mechanistic approaches, and identification of new compounds capable of altering Panx1 function, we expect to provide exciting new insights on pannexin channels and purinergic signaling in vascular physiology and hypertension, and the basis for novel treatment strategies targeting the regulated opening and closing of these channels in specific disease states. We expect our studies have a broad impact to cardiovascular, metabolic, and and respiratory diseases.